Presence of Autoreactive, MHC Class I-Restricted, Calcium-Sensing Receptor (CaSR)-Specific CD8+ T Cells in Idiopathic Hypoparathyroidism

Abstract

Context: Major histocompatibility complex class I allele HLA-A*26:01 and human leukocyte antigen (HLA) supertype A01 (STA01) are increased in idiopathic hypoparathyroidism (IH). However, cell-mediated autoimmune responses directed against the calcium-sensing receptor (CaSR) have not been demonstrated.

Objective: To study CaSR-specific cytotoxic T-cell responses in peripheral blood mononuclear cells of IH patients.

Design: Twenty-four peptides of CaSR (RH1 to RH24) were evaluated for their ex vivo potential to stimulate PBMCs from IH patients and controls in interferon (IFN)-γ enzyme-linked immunospot (ELISPOT) assays.

Setting: Tertiary patient care center and National Institute of Immunology, New Delhi, India.

Patients and other participants: Forty-five patients with IH attending the endocrine clinic of the All India Institute of Medical Sciences and 22 healthy controls.

Main outcome measures: Major histocompatibility complex class-I restricted, CaSR-specific cytotoxic CD8+ T-cell responses evaluated by IFN-γ ELISPOT assay.

Results: Of IH patients, 82.2% showed IFN-γ-secreting cells when stimulated ex-vivo with CaSR peptides. Peptides RH7, RH9, and RH16 elicited HLA supertype A01-restricted responses in IH. RH8, RH14, RH15, RH20, and RH21 peptides induced significantly higher responses in STA01+ IH patients compared with healthy controls irrespective of their supertype A01 status.

Conclusions: Our ex vivo IFN-γ ELISPOT assays demonstrate the presence of CaSR-specific memory CD8+ T cells in the peripheral circulation of patients with IH, suggesting the role of cell-mediated autoimmune responses in the etiopathogenesis of IH.